Obesity is associated with nonalcoholic fatty liver disease (NAFLD). NAFLD is a risk factor for insulin resistance and cardiovascular diseases, and leads to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. Hepatic steatosis is believed to be the first hit, and the second hit (e.g. oxidative, ER and oxidative stress) is aso required for NAFLD/NASH progression. However, the interplay of the first and second hits and the underlying mechanism of NAFLD/NASH progression remain unclear. In the preliminary study, we identified Snail2 as a novel regulator of lipid metabolism that is required for NAFLD in obesity. Snail2 is a transcriptional regulator believed to promote epithelial-to-mesenchymal transition (EMT) in development and cancer metastasis. It may also regulate proliferation and apoptosis in some cell types; however, its metabolic function has not been explored prior to this work. We show that the expression of hepatic Snail2 markedly increases in obesity. Genetic deletion of Snail2 prevents NAFLD, reduces liver oxidative, ER, and inflammatory stress, and improves insulin resistance and glucose intolerance in mice with either dietary or genetic obesity. Snail2 appears to perform dual actions, repressing the genes involved in fatty acid oxidation and activating the genes involved in lipid synthesis and uptake. In the current study, we will extend these observations to firmly establish the essential role of hepatic Snail2 in NAFLD progression and insulin resistance by generating and characterizing hepatocyte-specific Snail2 knockout or overexpressing mice. We will determine whether metabolic, oxidative, ER, and inflammatory stress increase the levels (via transcription and stability) and activity (via posttranslational modifications) of hepatic Snail2, which in turn promotes steatosis by increasing lipid synthesis and lipid uptake and decreasing oxidation. We will determine whether hepatic Snail2 connects the first and the second hits, and forms a hepatocellular stress-Snail2 vicious cycle that drives NAFLD progression in obesity. We will elucidate the mechanism by which hepatic Snail2 activates or represses the genes that control lipid synthesis, lipid uptake, and oxidation, and test the hypothesis that hepatic Snail2 genetically reprograms lipid pathways in the setting of obesity. The impact of this study lies in establishing a novel metabolic function of hepatic Snail2 and testing the novel concept that the hepatocellular stress-Snail2 vicious cycle drives NAFLD progression. The outcome is expected to lead to new therapies for NAFLD by targeting hepatic Snail2. PUBLIC HEALTH RELEVANCE: The prevalence of obesity is increasing rapidly. Obesity is associated with nonalcoholic fatty liver diseases (NAFLD). NAFLD leads to nonalcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, and type 2 diabetes. Unfortunately, the underlying mechanism of obesity-induced NAFLD is unclear, which limits our ability to treat these diseases. In this study, we will establish a novel concept that a hepatocellular stress- Snail2 vicious cycle drives NAFLD progression. Thus, the outcome is expected to lead to a new treatment for NAFLD, NASH, cirrhosis, and type 2 diabetes by breaking this cycle.